Patients With Multiple Myeloma or Monoclonal Gammopathy of Undetermined Significance

Diagnosis, Treatment, and Follow-Up

Background: Multiple myeloma (MM) is a malignant plasma-cell disease that arises on the basis of a so-called monoclonal gammopathy of undetermined significance (MGUS). The median age at disease onset is over 70. In Germany, there are approximately eight new cases per 100 000 inhabitants per year, or about 6000 new patients nationwide each year.

Methods: To prepare this clinical practice guideline, a systematic literature review was carried out in medical databases (MEDLINE, CENTRAL), guideline databases (GIN), and the search portal of the German Institute for Quality and Efficiency in Health Care (IQWiG). The recommendations to be issued were based on two international guidelines, 40 dossier evaluations and systematic reviews, 10 randomized controlled trials, and 37 observational studies and finalized in a structured consensus process.

Results: Because of its prognostic relevance, the use of the International Staging System (ISS) is recommended to stage MM and related plasma-cell neoplasms. When symptomatic MM is diagnosed, it is recommended to determine the extent of skeletal involvement by whole-body computed tomography. The indications for treatment shall be determined on the basis of the SLiM-CRAB criteria; in all patients with MM it is recommended to include the biological (rather than chronological) age in the decision-making process. In suitable patients, it is recommended that initial treatment includes high-dose therapy, followed by maintenance treatment. Even without high-dose treatment, a median progression-free survival of more than three years can be achieved with combination therapies. For the treatment of relapse, combinations of three drugs are more effective than doublet regimens with a median progression-free survival ranging from 10 to 45 months, depending on the study and prior therapy. Following anti-myeloma therapy, it is recommended to promptly offer physical exercise adapted to individual abilities to all patients who have the potential for rehabilitation, so that their quality of life can be sustained and improved.

Conclusion: This new clinical practice guideline addresses, in particular, the modalities of care that can be offered in addition to systemic antineoplastic therapy. In view of the significant recent advances in the treatment of myeloma, affected patients’ quality of life now largely depends on optimized interdisciplinary care.

Multiple myeloma (MM) is a malignant plasma cell disease and the second most common hematologic malignancy (1). It undergoes a more or less obligatory development from a precancerous condition called monoclonal gammopathy of unknown significance (MGUS) and is characterized by nonspecific symptoms, such as fatigue or diffuse aches and pains in the limbs. The incidence of MM in Germany is around eight new cases per 100 000 inhabitants per year, with a median onset age at diagnosis of >70 years (as of 2018; [2]). Between 1990 and 2016, the incidence rate has increased by 126% worldwide and is still rising, due in part to the growing and aging global population (2). In Germany, there were around 6350 new cases and 4180 deaths in 2018 (3).

Treatment options are constantly changing, with newly introduced drug groups and combinations that can be administered sequentially. So, although MM is not curable in most patients, it is now possible to achieve responses lasting several years. To provide a comprehensive, patient-centered management using these improved treatment options entails new challenges for diagnostics, prevention of complications, and symptom control.

The S3 consensus guideline, which has been prepared for the first time for Germany, compiles the current knowledge on this extensive topic and derives standards for the diagnosis and treatment of patients with MGUS and MM.

Methods

The S3 guideline was developed by an interdisciplinary group of clinicians, methodologists, patient representatives, and representatives of 25 professional societies and both German MM study groups (German-Speaking Myeloma Multicenter Group [GMMG], German Study Group Multiple Myeloma [DSMM]) under the auspices of the German Society of Hematology and Oncology (DGHO). It is published by the German Guideline Program in Oncology (GGPO) of the Association of the Scientific Medical Societies (AWMF) in Germany, the German Cancer Society (DKG), and the German Cancer Aid (DKH). The participating professional societies and experts are listed in the eBox.

eBox

Professional societies, organizations, experts and participants

After defining key questions and patient-relevant endpoints, a literature review was conducted (carried out by V. P., the eTable presents the search strategy). The results of the literature search were evaluated on the basis of their methodological quality. The quality of the evidence was assessed using the GRADE approach (“Grading of Recommendations, Assessment, Development and Evaluation Approach”) (4). The recommendation strength of statements and recommendations that were not evidence-based was decided by expert consensus of the guideline group.

eTable

Drug overview of the indications approved for adult patients with multiple myeloma according to drug product information

A detailed description of the methods, including how conflicts of interest were managed, can be found in the guideline report (5).

Results

The literature review identified 28 557 publications of potential relevance. Of these, two guidelines, 40 (41 references) systematic reviews with meta-analysis and dossier evaluations, ten randomized controlled trials, and 37 (38 references) prospective or retrospective studies were used to answer the key questions. The process of literature identification is presented graphically in eFigure 3. Since no adequate studies were identified for many of the key questions, the recommendations were based on expert consensus in this case.

eFigure 3

Presentation of the literature search

The long version, short version, and guideline report can be accessed on the AWMF and GGPO websites and are available digitally via the GGPO guideline app (6, 7, 8). A patient guideline is currently in progress.

Diagnostics and staging classification

Staging classification and prognostic assessment

If a monoclonal paraprotein is detected in serum or urine, then MM and other hematologic diseases should first be excluded (expert consensus), see Box. MGUS is characterized by the presence of a paraprotein without evidence of hematologic disease. MM is defined by the detection of at least 10% atypical clonal plasma cells on bone marrow examination. Differentiation of MM from related plasma cell neoplasms should be based on prognostic and therapeutic differences (expert consensus). The International Staging System (ISS) of the International Myeloma Working Group (IMWG) is recommended for staging, while the revised ISS (R-ISS) should be used when genetic findings are available (expert consensus).

Box

WHO classification of plasma cell neoplasms

Molecular cytogenetics

Multiple myeloma has many genetic alterations (10) which distinguish it from other lymphoid neoplasms with monoclonal gammopathy and allow for risk stratification (11, 12, 13). With MM, prior to commencing treatment, fluorescence in situ hybridization (FISH) should be performed on the CD138-positive plasma cells of the bone marrow aspirate, enriched by magnetic cell sorting to detect high-risk chromosomal alterations (1q gains, t(4;14) translocations or FGFR3-IGH fusion, t(14;16) or IGH-MAF fusion, and t(14;20) or IGH-MAFB fusion, 17p-deletion [TP53 gene]) (expert consensus) (Figure 1).

Figure 1

High-risk chromosomal abnormalities in multiple myeloma

Establishing the diagnosis

If MM is suspected, total protein quantification, protein electrophoresis with M gradient determination, immunofixation, and free light chain analysis in serum are required in addition to patient history and physical examination (expert consensus). The M gradient represents a pathological additional spike on serum electrophoresis, usually in the gamma globulin fraction region. Further laboratory tests should reveal significant organ dysfunction (for example, renal failure) and myeloma-associated features (for example, degree of antibody deficiency).

In addition, a bone marrow biopsy should also be obtained (expert consensus). Organ biopsies other than bone marrow are only performed if organ involvement or extramedullary myeloma manifestations are suspected. Full-body computed tomography (CT) should be obtained if MM is suspected and in patients with non-IgM MGUS (IgM, immunoglobulin-M) who have both a serum M protein >1.5 g/dL and an abnormal light chain ratio (expert consensus). In patients with solitary plasmacytoma, whole-body magnetic resonance imaging (MRI) or 18-fluorodeoxyglucose positron emission tomography (PET/CT) should be used to identify additional MM manifestations (recommendation grade: A) (Figures 2a and b). However, whole-body MRI and PET examinations are not included in the list of services covered by the statutory health insurance funds; reimbursement is therefore not guaranteed.

Figure 2

Female patient, 65 years old at time of imaging studies; progression from SMM to MM

The SLiM-CRAB criteria of the IMWG define MM requiring treatment. In addition to plasma cell infiltration of at least 10%, these criteria include evidence of MM-related end organ damage (hypercalcemia, renal failure, anemia, or bone lesions) or one or more myeloma-defining biomarker(s) (i.e., clonal plasma cell content in bone marrow ≥60%, serum free light chain ratio [affected/unaffected] ≥100, or >1 focal lesion >5 mm on whole-body MRI imaging). Involvement of focal lesions includes at least one well-circumscribed destruction of mineralized bone typical of myeloma or at least two foci typical of myeloma >5 mm on MRI or CT, or at least one lesion with concomitant osteolysis on PET-CT (eFigure 1).

eFigure 1

First-time appearance of osteolysis in the left iliac bone (arrow) on native computed tomography

A CT scan should be obtained to detect skeletal damage. Cushioning the arms may result in better CT image quality by avoiding beam hardening artifacts (expert consensus). Conventional skeletal survey radiographs should be avoided (expert consensus) and performed only when clinically indicated. Supplemental whole-body MRI or PET-CT may be performed to assess bone marrow involvement and possible extramedullary foci (expert consensus). If whole-body CT fails to show osteolysis, whole-body MRI, or alternatively MRI of the spine and pelvis, should be performed (expert consensus) (eFigure 2). PET/CT may be obtained instead of whole-body MRI (expert consensus). The relevance of both modalities for assessing response or progression is currently being further assessed in studies.

eFigure 2

Male patient, 59 years of age, initial diagnosis of multiple myeloma, staging before initiation of therapy, has multiple focal lesions, for example in the right dorsal iliac bone, visualized on MRI as well as on PET

Initiating therapy

The SLiM-CRAB criteria of the IMWG serve as the basis for the initiation of therapy (13). In addition to the SLiM-CRAB criteria, the presence of other symptoms may necessitate therapy (for example, recurrent infections, hyperviscosity syndrome, tumor pain, paraneoplastic polyneuropathy). MGUS with organ dysfunction requires a biopsy of the affected organ to be performed (expert consensus) and for example in case of renal involvment should be treated as monoclonal gammopathy of renal significance (MGRS), (expert consensus). Treatment should also be initiated in the presence of AL amyloidosis or light chain deposition disease (LCDD) (expert consensus).

In all patients with MM, biological age should be used instead of chronological age when making treatment decisions (expert consensus). For this purpose, the patient’s general condition, comorbidities, physical activity, and social integration should be taken into account – for example, by using the Karnofsky Index, according to the Eastern Cooperative Oncology Group (ECOG) status, or by using myeloma-validated comorbidity scores, such as the R-MCI (Freiburger Revised Myeloma Comorbidity Index) or the IMWG-FI (International Myeloma Working Group Frailty Index). Estimation of acceptable treatment intensity should also be reassessed after initiating therapy (expert consensus). The selection of options and intensity for systemic therapy has been well described in various previous resources (14, 15, 16). Systemic therapy is aimed at suppressing myeloma activity over as long a period as possible and is therefore usually continued as maintenance therapy until it becomes ineffective or intolerable—either as a constant combination of different drugs or as a sequence of combinations, for example induction, consolidation, maintenance. According to data from the Robert Koch Institute, the five-year relative survival rate in 2018 was 54% for females and 52% for males (2).

Selecting appropriate therapy

There is an ever-increasing choice of agents and modalities available for the treatment of multiple myeloma. Due to the large number of possible combinations, it is becoming increasingly difficult to provide evidence-based recommendations, especially since direct comparative studies are often lacking. Therefore, the following constitutes recommendations for a therapeutic strategy.

High-dose therapy and stem cell transplantation

Patients eligible for high-dose therapy should initially receive combination therapy to reduce disease activity (induction therapy) (recommendation grade: A) (overall survival after induction therapy followed by high-dose therapy and autologous stem cell transplantation as compared with drug therapy: hazard ratio [HR]: 0.76; 95% confidence interval: [0.42; 1.36]; progression-free survival [PFS]: HR 0.55 [0.41; 0.74]); result of a meta-analysis of four trials [2421 patients]) (17). This recommendation is based on the clinically relevant and statistically significant improvement in PFS. Given the very good treatment options for relapse, there is no statistically significant advantage in overall survival. General health should be used to assess transplant eligibility rather than chronological age (recommendation grade: B). This assessment should be reviewed on completion of induction treatment (expert consensus). Patients should receive a triple or quadruple combination as induction therapy (recommendation grade: A) (overall survival of a triple combination as compared with a quadruple combination: HR 1.04 [0.91; 1.19]; result of a meta-analysis of five trials [1765 patients]; overall survival of a quadruple combination as compared with a triple combination: HR 0.43 [0.23; 0.80], result of a randomized controlled trial [1085 patients]) (18,19). As yet, there is insufficient evidence to support any particular regimen or specific number of cycles, as not all combinations have been comparatively assessed.

Melphalan should be avoided during induction therapy in patients in whom high-dose therapy cannot be ruled out (expert consensus). Prolonged induction therapy prior to harvesting of stem cells (>4–6 cycles) should also be avoided, especially if it involves lenalidomide or other immunomodulatory agents (expert consensus).

Drug therapy

All patients should be offered maintenance therapy with lenalidomide after high-dose therapy and autologous stem cell transplantation (recommendation grade: A) (overall survival after autologous stem cell transplantation with lenalidomide maintenance therapy as compared with placebo maintenance or no maintenance therapy: HR 0.75 [0.63; 0.90]; result of a meta-analysis of three trials [1208 patients]) (20). Maintenance therapy should last at least two years and should be continued until disease progression (recommendation grade: A).

Non-transplant patients should receive continuous therapy (recommendation grade: A) and should be treated initially with a triple or quadruple combination in the absence of serious comorbidities (recommendation grade: B). All tested combinations have demonstrated a clinically relevant and statistically significant advantage, not only with regard to PFS but also to overall survival. A list of prospective randomized treatment modalities is compiled in the Table, and an overview of the individual drugs approved for MM is provided in the eTable. However, an optimal therapeutic regimen cannot be provided due to the lack of comparative studies. The US American Society of Cancer (ASCO) guideline, the joint European Haematology Association (EHA), European Society for Medical Oncology (ESMO) guideline, and the IMWG guideline provide compilations on the manifold treatment options (16, 21, 22).

Table

Randomized comparative studies on the therapy of multiple myeloma (in alphabetical order)

Radiotherapy

In cases of multiple involvement, radiotherapy should be used to treat osteolytic bone lesions to prevent local complications (for example, fractures) or to treat intractable pain resulting from osseous or non-osseous involvement (expert consensus). Radiotherapy can be administered simultaneously with systemic (maintenance) therapy, although this should be done in close consultation with a medical oncologist (expert consensus). Treatment of solitary plasmacytoma is by radiotherapy. This is achieved by applying a dose of between 40 and 50 Gy (recommendation grade: B). Treatment with a dose lower than 40 Gy should not be given because of the significantly lower local control rate (recommendation grade: A) (overall survival after radiotherapy with ≥40 Gy as compared with <40 Gy: HR: 0.62 [0.54; 0.72]; result of a retrospective analysis of 2816 patients) (23). Radiotherapy should also be given following initial surgical treatment (e.g. for a pathological fracture) (expert consensus).

Therapy response and therapy continuation

Assessment of minimal residual disease (MRD)

Flow cytometry or genetic methods can be used to measure MRD in bone marrow. Studies have shown that MRD negativity resulted in significantly prolonged PFS (HR: 0.41 [0.36; 0.48]; 14 studies [1273 patients] included in meta-analysis) and overall survival (HR: 0.57 [0.46; 0.71]; 12 studies [1100 patients] included in meta-analysis) (statement) (20). However, there are no study results available to date evaluating MRD status as a basis for therapeutic decisions (MRD-guided treatment) (statement). Therefore, assessment of MRD status is reserved for clinical trials (recommendation grade: 0).

Consequences upon treatment response or in the event of an increase in disease activity

If progression is not otherwise suspected, MGUS with a high risk of progression, smoldering multiple myeloma (SMM), or successfully treated solitary plasmacytoma without evidence of persistent or systemic plasmacytic disease should undergo annual whole-body MRI or whole-body CT combined with MRI of the spine and pelvis over a period of five years (expert consensus).

High-dose therapy should be given in patients with MM regardless of response during induction therapy (recommendation grade: B). Free light chain assay should be used to classify treatment response in hyposecretory myeloma, and analysis of clonal plasma cell content in bone marrow or alternatively by serial imaging using whole-body MRI or PET-CT in non-secretory myeloma (expert consensus). If therapy only produces stable disease, then a change in therapy should be considered (expert consensus). Furthermore, therapy should be recommenced or changed (expert consensus)

• if new end-organ damage develops (according to CRAB criteria),
• in the case of progressive extramedullary disease or high dynamics of biochemical parameters,
• and in the case of disease progression during on-going therapy or early progression after the end of therapy.

If relapse occurs, therapy should be continued until progression, depending on initial response, tolerability, toxicity, and patient preference (recommendation grade: B). A variety of treatment options are available, with combinations of three substances being preferred over doublet combinations due to better efficacy (expert consensus). The Table lists tested and available combinations. Here, all triple combinations show improved PFS, and in some cases longer overall survival, although the studies are not comparable with each other due to different patient characteristics and differences in prior therapies.

Symptom control and follow-up rehabilitation

Patients with MM often suffer from bone pain secondary to skeletal involvement. Pain management should be provided according to the S3-consensus guidelines on palliative care, regardless of the disease stage (expert consensus) (24).

Antiresorptive agents (bisphosphonates or RANKL inhibitors [RANKL, Receptor Activator of NF-κB Ligand]) are used for bone manifestations to inhibit osteoclast activity. Substitution therapy with vitamin D and calcium should be given during RANKL inhibitor therapy in the absence of hypercalcemia, whereas it may be given optionally during bisphosphonate therapy (expert consensus), because hypocalcemia usually remains asymptomatic during bisphosphonate therapy.

Physical exercise has long been a subject of critical debate in patients with MM. However, studies have shown that physical activity is safe and can both improve quality of life and reduce symptom severity. Results of a Cochrane review showed, among other things, less fatigue after aerobic exercise compared with no aerobic exercise (mean improvement of 0.31 points [0.13; 0.48] on a scale of −1 to 1; nine studies [826 patients included in meta-analysis]). Improvement in quality of life with aerobic exercise is possible, but the evidence here is uncertain (mean difference of 0.11 points [0.03; 0.24] on a scale of −1 to 1; eight studies [1259 patients included in meta-analysis]) (25).

Therefore, after completion of myeloma-specific therapy, follow-up rehabilitation should be offered to all patients capable of undergoing rehabilitation (expert consensus). Physical exercise is well tolerated by patients, even in the acute treatment phase and even under high-dose therapy (26, 27, 28). Adjusted physical training should be offered to patients early (recommendation grade: B). The aim is to improve the quality of life of those affected and to help them regain an active and self-determined lifestyle.

Discussion

The S3-consensus guideline provides both evidence-based and consensus-based recommendations for the diagnostics, treatment, and follow-up of patients with MM and its specific manifestations, especially for care related to systemic therapy. The rapid further development of treatment options and the expected new comparative studies will require ongoing adaptation in the sense of a living guideline. Findings from key publications that modify recommendations should be integrated in a timely manner through annual update checks.

Acknowledgments

We would like to thank Prof. Dr. sc. hum. Anna Jauch, Institute of Human Genetics, Heidelberg University Hospital, and Prof. Stefan Delorme MD, German Cancer Research Center Heidelberg, Research Unit Imaging and Radiation Oncology, for providing us with the figures used.

Conflict of interest statement
Prof. Einsele has received consultancy fees and fees for lecture activities from the companies Janssen, Celgene, Bristol-Myers Squibb, Novartis and Takeda and serves as a scientific advisor to these companies. He received research funding from Bristol Myers Squibb/Celgene, Janssen, Amgen, GlaxoSmithKline and Sanofi.

Prof. Goldschmidt has received consultancy fees from the companies Adaptive Biotechnology, Amgen, Bristol-Myers Squibb, Celgene, Jannsen, Sanofi and Takeda. He has received payment for authorship from the companies Amgen, Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Janssen, Novartis and Sanofi. He received research funding from the companies Novartis, MorphoSys, Glycomimetics, HD Pharma, Amgen, Takeda IQVIA, Celgene, GlaxoSmithKline and OIS.

Prof. Scheid has received consultancy fees from the University Hospital Cologne Management and from the companies Novartis, Amgen, Janssen, Celgene, Bristol-Myers Squibb and Takeda. He received fees for lecture activities from the companies Novartis, Amgen, Janssen, Celgene, Bristol-Myers Squibb and Takeda. He has received study support (third-party funds) for carrying out commissioned studies for the companies Janssen, Bristol-Myers Squibb, Takeda, Pfizer and Amgen. He received research funding from the companies Novartis, Takeda and Janssen.

Prof. Engelhardt has received consultancy fees and fees for lecture activities from the companies Amgen, Bristol-Myers Squibb, Takeda, Sanofi, GlaxoSmithKline and Janssen. He received research funding from the companies Janssen, Amgen and Bristol-Myers Squibb.

The other authors declare that no conflict of interest exists.

Manuscript received on 23 November 2021, revised version accepted on 10 February 2022

Translated from the original German by Dr. Grahame Larkin, MD

As with many other professional journals, clinical guidelines in Deutsches Ärzteblatt are not subject to the peer review process, as S3 guidelines are texts that have been assessed and discussed by experts (peers) and already enjoy a broad consensus.

Corresponding author
Prof. Dr. h. c. Christof Scheid MD

Klinik I für Innere Medizin

Universitätsklinikum Köln

Kerpener Straße 62, 50937 Köln, Germany

Cite this as:
Piechotta V, Skoetz N, Engelhardt M, Einsele H, Goldschmidt H, Scheid C: Clinical practice guideline: Patients with multiple myeloma or monoclonal gammopathy of undetermined significance—diagnosis, treatment, and follow-up. Dtsch Arztebl Int 2022; 119: 253–60. DOI: 10.3238/arztebl.m2022.0149

►Supplementary material

eReferences, eFigures, eBox, eTable:
www.aerzteblatt-international.de/m2022.0149

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